BOSTON—Ziopharm Oncology Inc. in mid-November provided an update on its Controlled IL-12 platform following a presentation of positive data from its Phase 1 clinical trial in recurrent glioblastoma (rGBM) at the Society for Neuro-Oncology (SNO) annual meeting in New Orleans.
Ziopharm is developing Controlled IL-12—or Ad-RTS-hIL-12 plus veledimex, a gene therapy that controls the expression of interleukin 12 (IL-12)—for the treatment of rGBM as both a monotherapy and in combination with immune checkpoint inhibitors. The company is driving this platform forward to secure a development partner in support of registrational trials.
Phase 1 data have shown that Ad-RTS-hIL-12 with a 20 mg dose of veledimex and less than 20 mg of the steroid dexamethasone is the preferred dosing regimen to treat patients with rGBM. When treating patients with Ad-RTS-hIL-12 plus veledimex, higher doses of steroids appear to suppress the immune response and negatively affect survival compared to low-dose steroids.
Ziopharm has enrolled 15 patients in an expansion of its Phase 1 trial designed to further evaluate preferred dosing of Ad-RTS-hIL-12 with 20 mg of veledimex as monotherapy with guidance on minimal dosing of steroids. This expansion cohort for this study, which was initiated in the third quarter of 2018, is accruing rapidly and is expected to be fully enrolled with at least 25 patients in the first quarter of 2019.
The company is advancing Controlled IL-12 as a combination therapy with PD-1 inhibitors, and is enrolling the second dosing cohort in a Phase 1 trial to evaluate Controlled IL-12 in combination with the PD1 inhibitor Opdivo (nivolumab). The company expects to begin a Phase 2 trial to evaluate Ad-RTS-hIL-12 plus veledimex in combination with Regeneron Pharmaceuticals’ PD-1 antibody Libtayo (cemiplimab-rwlc) in the first half of 2019.
Ziopharm has enrolled more than 100 patients with Ad-RTS-hIL-12 plus veledimex and administered more than 1,300 doses of veledimex across three types of solid tumors, building what it calls “a significant safety profile and mechanistic dataset.” Biopsy data reportedly demonstrated that Controlled IL-12 turns immunologically “cold” tumors “hot” based on sustained infiltration of killer T cells, which is likely responsible for the improved survival associated with Controlled IL-12 used as monotherapy in patients with rGBM. Biopsy data also revealed upregulation of immune checkpoints providing what Ziopharm deems “compelling rationale” for combining with PD-1 inhibitors. The immunologic mechanism of action of IL-12 is likely the reason elevated doses of steroids may reduce its activity.
Data presented at SNO 2018 were generated from the company’s Phase 1 monotherapy trial, which evaluates two methods of administration of Ad-RTS-hIL-12, explores the dosing of veledimex and evaluates the impact of steroids.
Ad-RTS-hIL-12 plus veledimex continues to be well tolerated, according to Ziopharm, with related adverse events reversible across all cohorts upon stopping the oral administration of veledimex. A sub-analysis of patient data in the 20 mg veledimex craniotomy cohort shows that reduced dosing of the steroid dexamethasone had a positive impact on survival compared to higher doses in patients that received Controlled IL-12 via craniotomy or stereotactic injection. Six patients who received 20 mg or less of dexamethasone cumulatively over 15 days had median overall survival (mOS) of 17.8 months, compared to 6.4 months mOS for patients who received more than 20 mg of dexamethasone during the same observation period. The entire cohort of 15 patients that received 20 mg veledimex had mOS of 12.7 months with a mean follow up of 13.1 months. These data, Ziopharm says, support continued development of Controlled IL-12, especially considering the benchmark mOS of five to eight months for patients with rGBM that serves as historical controls.
“Glioblastoma at recurrence is a dreadful cancer with few treatment options that have demonstrated success. These updated data show a promising extension of patients’ survival and demonstrate how controlling the powerful cytokine IL-12 can engage the body’s own immune system to generate an antitumor response against rGBM,” said Dr. Antonio Chiocca, lead author of the poster presented at SNO 2018. Chiocca is a professor of neurosurgery at Harvard Medical School, surgical director of the Center for Neuro-oncology at Dana-Farber Cancer Institute and chairman of neurosurgery, as well as co-director of the Institute for the Neurosciences at Brigham and Women's Hospital.